Naltrexone is an opioid receptorantagonist used primarily in the management of alcohol dependenceand opioid dependence. It is marketed in generic form as itshydrochloride salt, naltrexone hydrochloride, and marketed under the trade names Revia andDepade. In some countries including the United States, a once-monthly extended-release injectable formulation is marketed under the trade name Vivitrol. Also in the US,Methylnaltrexone Bromide, a closely related drug, is marketed asRelistor, for the treatment of opioid induced constipation.
Naltrexone should not be confused with naloxone (which is used in emergency cases of overdoserather than for longer-term dependence control) nor nalorphine. Both nalorphine and naloxone are full antagonists and will treat an opioid overdose, but nalorphine is longer-acting than naloxone (although neither is an irreversible antagonist like naloxazone), making naloxone a better emergency antidote.
Medical uses
Alcohol dependence
The main use of naltrexone is for the treatment of alcohol dependence. After publication of the first two randomized, controlled trials in 1992, a number of studies have confirmed its efficacy in reducing frequency and severity of relapse to drinking. The multi-center COMBINE study has recently proven the usefulness of naltrexone in an ordinary, primary care setting, without adjunct psychotherapy. Mechanism of action may be antagonism to endogenous opiates such as tetrahydropapaveroline, whose production is augmented in the presence of alcohol.
The standard regimen is one 50 mg tablet per day. Initial problems of nausea usually disappear after a few days, and other side effects (e.g., heightened liver enzymes) are rare. Drug interactions are not significant, besides the obvious antagonism of opioid analgesics. Naltrexone has two effects on alcohol consumption. The first is to reduce craving while naltrexone is being taken. The second, referred to as the Sinclair Method, occurs when naltrexone is taken in conjunction with normal drinking, and this reduces craving over time. The first effect persists only while the naltrexone is being taken, but the second persists as long as the alcoholic does not drink without first taking naltrexone.
Roy Eskapa, who wrote a book advocating the Sinclair Method, argues that Naltrexone does not work in conjunction with abstinence. Eskapa cites as evidence a Finnish clinical trial in which "Naltrexone tended to be worse than those for placebo," and two studies that produced "almost identical graphs": an alcoholism clinical trial at Yale and a Naltrexone for cocaine addiction trial at the University of Texas.
Depot injectable naltrexone (Vivitrol, formerly Vivitrex, but changed after a request by the FDA) was approved by the FDA on April 13, 2006 for the treatment of alcohol dependence. This version is made and marketed by Alkermes in the United States, and is marketed by Johnson & Johnson in Russia. Cephalon Inc. originally marketed the drug in the United States, however, Alkermes reclaimed Vivitrol commercialization rights in 2008. The recommended dose of Vivitrol 380 mg is delivered intramuscularly once a month. The injection should be administered by a healthcare professional.
The clinical trial that the approval of Vivitrol was based on showed that when compared with a placebo, 380 mg of Vivitrol resulted in a 25% decrease in the event rate of heavy drinking days and 190 mg resulted in a 17% decrease. The 6-month randomized, double-blind, placebo-controlled study was conducted between February 2002 and September 2003. Of the 899 individuals screened, 627 were diagnosed as alcohol-dependent adults and were randomized to receive treatment. The main outcome measure was the event rate of heavy drinking days in the intent-to-treat population. The study’s authors concluded that: “Long-acting naltrexone was well tolerated and resulted in reductions in heavy drinking among treatment-seeking alcohol dependent patients during 6 months of therapy.
A naltrexone treatment study released by the National Institute of Health in February 2008 and published in the Archives of General Psychiatry has shown that alcoholics having a certain variant of the opioid receptor gene (G polymorphism of SNP Rs1799971 in the gene OPRM1) demonstrated strong response to naltrexone and were far more likely to experience success at cutting back or discontinuing their alcohol intake altogether, while in those lacking the gene variant, naltrexone appeared to be no different from placebo. The G allele of OPRM1 is common in individuals of Asian descent, with 60% to 70% of people of Chinese, Japanese, and Indian ancestry having at least one copy, as opposed to 30% of Europeans and very few Africans. In line with this finding, studies found naltrexone to be more efficacious among white subjects than among black subjects, and a 2009 study of naltrexone as an alcohol dependence treatment among African Americans failed to find any statistically significant differences between naltrexone and placebo.
Opioid dependence
Naltrexone helps patients overcome opioid addiction by blocking the drugs’ euphoric effects, similar to disulfiram in alcohol dependence. Unlike when used for alcohol dependence (discussed above), naltrexone has little effect on opiate cravings. Naltrexone has in general been better studied for alcohol dependence than in treating opioid dependence. It is also more frequently used for alcohol, despite originally being approved by the FDA in 1984 for opioid addiction.
A recent review of studies suggests that more studies are needed to show naltrexone's effectiveness in treating opioid dependence (and to compare naltrexone to other options such asmethadone and buprenorphine). While some patients do well with the oral formulation, there is a drawback in that it must be taken daily, and a patient whose cravings become overwhelming can obtain opioid intoxication simply by skipping a dose before resuming abuse. Due to this issue, the usefulness of oral naltrexone in opioid dependence is limited by the low retention in treatment. Oral naltrexone remains an ideal treatment only for a small part of the opioid-dependent population, usually the ones with an unusually stable social situation and motivation (e.g., dependent health care professionals). Naltrexone treats the physical dependence on opioids, but further psychosocial interventions (such as counselling and group therapy) are often required to enable people to maintain abstinence
The FDA approved a long-acting version of naltrexone (trade-named Vivitrol) on October 12, 2010 for the prevention of relapse to opioid dependence, following opioid detoxification. This injectable version was previously approved only for alcohol depencence. The phase 3 clinical study upon which the FDA granted approval for Vivitrol in treating opioid dependence had an enrollment of 250 patients and treated for six months. Primary outcome measures were percentage of weekly urine tests negative for opioids and length of study retention during the double-blind period. Alkermes presented positive results from this study at the American Psychiatric Association 2010 Annual Meeting in May 2010. The study met its primary efficacy endpoint and data showed that patients treated once-monthly with Vivitrol demonstrated statistically significant higher rates of opioid-free urine screens, compared to patients treated with a placebo, as measured by the cumulative distribution of clean urine screens (p<0.0002).
“This drug approval represents a significant advancement in addiction treatment,” said Janet Woodcock, M.D., director of the FDA’s Center Drug Evaluation and Research. Nora Volkow, M.D., Director of the National Institute on Drug Abuse (NIDA), stated that: “As a depot formulation, dosed monthly, Vivitrol obviates the daily need for patients to motivate themselves to stick to a treatment regimen - a formidable task, especially in the face of multiple triggers of craving and relapse. This new option increases the pharmaceutical choices for treating opioid addiction, and may be seen as advantageous by those unwilling to consider agonist or partial agonist approaches to treatment. NIDA is continuing to support research on Vivitrol's effectiveness in this country, including a focus on criminal justice involved populations transitioning back into the community.”
A newer option is the naltrexone implant, which may be surgically inserted under the skin. The implant provides a sustained dose of naltrexone to the patient, thereby preventing the problems which may be associated with skipping doses. It must be replaced every several months. Naltrexone implants are made by at least three companies, though none have been approved by the U.S. Food and Drug Administration (FDA) or the Australian Therapeutic Goods Administration. Naltrexone implants have been used successfully in Australia for a number of years as part of a long-term protocol for treating opiate addiction.
Rapid opioid detoxification
Naltrexone is sometimes used for rapid detoxification ("rapid detox") regimens for opioid dependence. The principle of rapid detoxification is to induce opioid-receptor blockage while the patient is in a state of impaired consciousness, so as to attenuate the withdrawal symptoms experienced by the patient. Rapid detoxification under general anaesthesia (sometimes called "ultra-rapid detox") involves an unconscious patient and requires intubation and external ventilation. Rapid detoxification is also possible under lighter sedation. The rapid detoxification procedure is followed by oral naltrexone daily for up to 12 months for opioid dependence management. There are a number of practitioners who will use a naltrexone implant, usually placed in the lower abdomen, to replace the oral naltrexone. This implant procedure has not been shown scientifically to be successful in "curing" subjects of their addiction, though it does provide a better solution than oral naltrexone for medication compliance reasons. There is currently scientific disagreement as to the safety of this procedure, as well as whether this procedure should be performed under light sedation or general anesthesia, due to the rapid and sometimes severe withdrawal that occurs.
Rapid detoxification has been criticised by some for its questionable efficacy in long-term opioid dependence management. Rapid detoxification has often been misrepresented as a one-off "cure" for opioid dependence, when it is only intended as the initial step in an overall drug rehabilitation regimen. Rapid detoxification is effective for short-term opioid detoxification, but is approximately 10 times more expensive than conventional detoxification procedures. Aftercare can also be an issue, since at least one well-known center in the United States reported that they will remove an implant from any patient arriving in their facility before admission
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